Rivas Martin A, Melnick Ari M
Division of Hematology and Medical Oncology, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Sandra and Edward Meyer Cancer Center, New York, New York, USA.
Curr Opin Hematol. 2019 Jul;26(4):294-302. doi: 10.1097/MOH.0000000000000505.
Chromatin organization during interphase is nonrandom, and dictated by a delicate equilibrium between biophysics, transcription factor expression, and topological regulators of the chromatin. Emerging evidence demonstrate a role for chromosomal conformation at different stages of B-cell development. In the present review, we provide an updated picture of the current knowledge regarding how chromosomal conformation regulates the B-cell phenotype and how disruption of this architecture could lead to B-cell lymphoma.
B-cell development requires proper assembly of a rearranged VDJ locus, which will determine antigen receptor specificity. Recently, evidence pointed to a role for topological regulators during VDJ recombination. Research studies also demonstrated a link between shifts in nuclear chromosomal architecture during B-cell activation and in formation of germinal centers, which is required for immunoglobulin affinity maturation. Class-switch recombination was shown to be dependent on the presence of topology regulators. Loss of topological insulation of enhancers may lead to oncogene activation, suggesting that misfolding of chromatin may constitute a new epigenetic mechanism of malignant transformation. Finally, CCCTC-binding factor and cohesin binding sites have shown a higher probability of mutations and translocations in lymphomas, lending further support to the potential role of chromatin architecture in cancer development.
Chromosomal conformation is now recognized as a key feature in the development of a robust humoral immune response. Several examples from the literature show that dysregulation of chromosomal architecture may be a foundational event during malignancy. Therefore, understanding the mechanisms that regulate chromosomal folding and drive gene activation are instrumental for a better understanding of immune regulation and lymphomagenesis.
间期染色质组织是非随机的，由生物物理学、转录因子表达和染色质拓扑调节因子之间的微妙平衡所决定。新出现的证据表明染色体构象在B细胞发育的不同阶段发挥作用。在本综述中，我们提供了关于染色体构象如何调节B细胞表型以及这种结构破坏如何导致B细胞淋巴瘤的最新知识图景。
B细胞发育需要重排的VDJ基因座正确组装，这将决定抗原受体特异性。最近，有证据表明拓扑调节因子在VDJ重组过程中发挥作用。研究还表明，B细胞激活过程中核染色体结构的变化与生发中心的形成之间存在联系，而生发中心是免疫球蛋白亲和力成熟所必需的。类别转换重组被证明依赖于拓扑调节因子的存在。增强子拓扑绝缘的丧失可能导致癌基因激活，这表明染色质错误折叠可能构成恶性转化的一种新的表观遗传机制。最后，CCCTC结合因子和黏连蛋白结合位点在淋巴瘤中显示出更高的突变和易位概率，进一步支持了染色质结构在癌症发展中的潜在作用。
染色体构象现在被认为是强大的体液免疫反应发展中的一个关键特征。文献中的几个例子表明，染色体结构失调可能是恶性肿瘤发生过程中的一个基础事件。因此，了解调节染色体折叠和驱动基因激活的机制有助于更好地理解免疫调节和淋巴瘤发生。
